Inventors Lawrence Irwin Glass, Michael John Bickerdike, Michael Fredrick Snape, and Patricia Perez de Cogram.
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Quote: Discussion and Conclusions:
Poor social competencies and repetitive behaviors are the common features and key diagnostic measures of all forms of ASD. Delayed intellectual development and underdeveloped language skills are also a common feature present in all ASD, excluding Asperger syndrome.
The animal models described above have been accepted in the art as demonstrating similar symptoms to the clinical human conditions. All mutant models discussed above (NLGN3, NLGN4, CADM1, NRXN1, FMR1, shank3) exhibit impaired social skills or increased social anxiety. Decreased excitatory transmission into the hippocampus has been identified in NRXN1, shank3, MeCP2 and FMR1 mutant animal models. At present no polygenetic or multifactorial models of ASD have been described. The animal models described above, based on genetic defects that are known to produce ASD in human population, provide the best opportunity to test the efficacy of ASD therapies.
Therefore the efficacy of cG-2-AllylP in animal models of ASD is reasonably predictive of its efficacy in a human subject suffering from ASD.
And:
FIG. 28 depicts a graph of the time spent in “freezing behavior” for each of the groups of animals tested. Under acute stress conditions of this study, vehicle-treated wild-type animals (left bar) spent an average of about 30% of the five-minute test period (i.e., about 100 seconds). In contrast, vehicle-treated fmr1-knockout animals (second bar from left) spent substantially less time in freezing behavior (about 18% of the five-minute test period, or about 54 seconds). We conclude that the fmr1-knockout animals exhibited less fear than vehicle-treated wild-type animals.
We unexpectedly found that cG-2-AllylP (“NNZ 2591”) produced a substantial and statistically significant increase in the time spent in freezing behavior in fmr1-knockout animals (right bar). In fact, the time spent in freezing behavior observed for cG-2-Allyl P-treated fmr1-knockout animals was similar to the time spent by the vehicle-treated wild-type animals (left bar) and the cG-2-AllylP=treated wild-type animals (third bar from left).
Conclusions
We conclude from this study that fmr1-knockout animals exhibited lower fear conditioning than wild-type animals. This indicates that fmr1-knockout animals may have a survival disadvantage compared to wild-type animals. We also conclude that cG-2-AllylP increased fear conditioning in fmr1-knockout mice under these conditions. This effect may mitigate the survival disadvantage observed in vehicle-treated fmr1-knockout animals. Because the fmr1-knockout mice used in this study have the same genetic mutation as human beings with Fragile X Syndrome, we conclude that cG-2-AllylP can be effective in treating human beings with Fragile X Syndrome.
And:
Social recognition and social memory in mice were evaluated by the amount of time spent sniffing a novel mouse upon repeated exposures, to induce familiarity, and reinstatement of high levels of sniffing when a novel stimulus animal is introduced. We measured the number of bouts of sniffing in each of the groups of animals.
Results and Conclusions FIG. 30 depicts a graph of the duration of bouts of sniffing (vertical axis) for the different groups of mice studied. We found that vehicle-treated wild-type animals (left bar) exhibited bouts of sniffing of about 23 during the test period. In contrast, fmr1-knockout animals (second bar from left) exhibited less sniffing behavior (about 6).
We surprisingly found, however, that in cG-2-AllylP (“NNZ 2591”)-treated fmr1-knockout animals (right bar), the amount of sniffing behavior significantly increased to about 21 (p<0.001). In fact, cG-2-AllylP increased sniffing behavior in fmr1-knockout animals to about the same levels as in vehicle-treated wild-type (left bar) or cG-2-AllylP-treated animals (third bar from left).
We conclude that fmr1-knockout animals exhibited a deficit of sociability compared to wild-type animals. The results of this are consistent with the well-known deficits in sociability observed in human beings with Fragile X Syndrome. We also conclude that cG-2-AllylP increased sociability observed for fmr1-knockout mice, and normalized the behavior.
Because the fmr1-knockout mice used in this study have the same genetic mutation as human beings with Fragile X Syndrome, we conclude that cG-2-AllylP can be effective in improving social interactions in human beings with Fragile X Syndrome.
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